Method for preparing synthetic bone substitutes with controlled porosity

ABSTRACT

The invention concerns a method for preparing macro-porous synthetic ceramics designed in particular for bone substitution. The invention also concerns macro-porous synthetic ceramics comprising pores of controlled dimensions, distributed in number and in surface in a predetermined manner, the interconnection between the pores thereof being controlled.

BACKGROUND OF THE INVENTION

The invention relates to a process for preparing a macroporous syntheticceramic intended especially as a bone replacement, the ceramic having acontrolled interconnection dimension between the pores, as well as acontrolled porosity and a controlled pore size.

The processes of the aforementioned type, known from the prior art, havea number of drawbacks.

This is because these processes do not allow the porous architecture ofthe ceramic obtained to be completely controlled, namely especially tocontrol not only the size and shape of the macropores and theirdistribution within the ceramic matrix but also the size of theinterconnections between macropores.

Now, this lack of control reduces the biological effectiveness of theceramics, which is characterized, in the case of an application as abone replacement, by poor bone rehabilitation or, at the very least,partial rehabilitation of the bone replacement.

In addition, heterogeneities in the mechanical behaviour, especially incompression, are often found because of the imperfect reproducibility ofthe architectures.

Certain processes recommend exerting pressure on the compacted particlesintended to form the pores, so as to control the interconnectiondiameter.

However, this type of process does not allow effective control of theinterconnection, which is homogeneous, easily reproducible andmodifiable.

Moreover, the structural heterogeneities in the ceramic bonereplacements of the prior art often cause variations in the mechanicalbehaviour.

Because the architectures are not completely controlled, the mechanicalstrength is often low, particularly in compression. It is necessary tolimit the mechanical stresses on the implant and, consequently, toreduce the size of the manufactured components for the purpose oflimiting the risk of mechanical failure of the implant/receiving bonesystem.

The prior art is represented, in particular, by documents WO-A-92/06653,DE-A-4,403,509, DE-A-3,123,460 and WO-A-95/32008.

SUMMARY OF THE INVENTION

The object of the invention is therefore to alleviate the drawbacks ofthe aforementioned prior art.

Thus, one objective of the process of the invention is especially:

to control the interconnection between the macropores of a syntheticceramic in a reproducible and modifiable manner so as, in particular, toallow the passage of bone cells and thus to ensure bone neoformationright into the core of the biomaterial in the case of an application asa bone replacement, this control of the interconnection having to beimplemented in a homogeneous manner and right into the core of thereplacement, whatever its size;

to control the porosity of the ceramic and the dimensions of the pores;

to produce biocompatible ceramics, “on request”, having dimensions and apredefined shape.

For this purpose the invention proposes a process of the aforementionedtype, characterized by the following successive steps:

a) construction of an edifice from pore-forming elements;

b) thermoforming of the edifice so as to ensure controlled coalescencebetween the pore-forming elements;

c) impregnation of the edifice with a suspension so as to fill thespaces between the pore-forming elements;

d) removal of the pore-forming elements so as to generate themacroporosity with a controlled interconnection diameter.

More specifically, according to the process of the invention, particlesof a pore-forming organic compound of low thermal expansion are packedinto a container, the particles having a predetermined shape.

In order for there to be intimate contact between the particles, andtherefore for the interconnection between macropores to be generated,the particles are subjected to a thermoforming treatment.

The purpose of this operation is to reach the working temperature,greater than the glass transition temperature of the organic compound,so as to place it in its rubbery plateau, so as to produce controlledwelding between these particles.

The generation of the controlled bridging between particles, andtherefore of the future controlled interconnection between macropores,is achieved by regulating the thermoforming treatment time parameter andthe thermoforming treatment temperature parameter.

Other approaches are possible if it is desired to reduce the treatmenttime. It is possible, for example, to increase the working temperature(without however reaching the decomposition temperature of the polymer)or else to apply pressure to the polymeric edifice (at a temperatureabove the glass temperature) so as to speed up the development of thewelds which form.

Once the connections have been made between the particles, the monoblocformed by these interconnected particles is extracted, after thestructure has cooled, in order to place it in a porous mold.

The spaces between the particles are then filled up with a calciumphosphate powder in suspension in an aqueous medium so as to form theceramic reinforcement of the material.

After removing the water via the porous structure of the mold, theproduct obtained is demoulded and then heat-treated so as, in a firststep, to remove the organic compound, and therefore to generate theporosity of the product, and then, in a second step, to densify thewalls of the ceramic.

According to the invention, the organic compound is chosen especiallyfrom acrylic resins, such as, in particular, polymethyl methacrylate(PMMA) and polymethacrylate (PMA), polystyrene, polyethylene or similarmaterials.

Furthermore, in one embodiment of the invention, the particles have anapproximately spherical general shape.

According to the invention, the calcium phosphate is chosen especiallyfrom hydroxyapatite (HA) or tricalcium phosphate (β TCP), or the like,or a mixture of them.

The process of the invention thus makes it possible to obtain amacroporous synthetic ceramic whose interconnection between macroporesis perfectly controlled and whose pores have controlled dimensions andare distributed, in terms of number and area, in a predetermined manner.

More specifically, the process of the invention allows perfect controlof the diameter of the spherical pores, especially between 100 μm and800 μm, with perfectly controlled interconnections, especially between0.1 and 0.8 times the diameter of the macropore involved, and moreparticularly between 40 and 640 μm.

Moreover, control of the parameters, such as the treatment temperature,the treatment pressure and the treatment time, allows theinterconnection diameter to be controlled.

A polymer redistribution law at a temperature above the glass transitiontemperature, of the viscous-flow type, for the formation ofinterparticle necks, governs the coalescence of the particles and thusallows the final interconnection diameter to be perfectly controlled.

For experimental implementation reasons, ceramics are produced in whichthe interconnection diameter between the macropores is greater than 30μm. Consequently, for each given particle-size class of beads, thecoalescence, and therefore the final interconnection of the product, canbe precisely adjusted. It should be understood that these two parametersare distinct from each other and can be adjusted independently.

The invention also makes it possible to obtain ceramics of theaforementioned type in any size, whether these are small or large(several cm³), and having a high mechanical strength.

Furthermore, this process also makes it possible to obtain ceramics thatcan be bone replacements of complex shape and of constant or variableporosity.

Finally, according to another aspect, the invention relates to the useof such a ceramic as a bone replacement.

Other features and advantages of the invention will emerge from thedescription that follows, with reference to the appended drawings andillustrations.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an electron microscope image showing the coalescence ofpolymer particles.

FIG. 2 is an electron microscope image of a monobloc structure formedfrom the interconnected particles.

FIGS. 3 and 4 are electron microscope images of ceramics containing 500μm pores, the interconnection diameters of which are 100 μm and 200 μm,respectively.

FIG. 5 is an electron microscope image of particles that have undergonea heat treatment at 150° C.

FIGS. 6a to 6 c are diagrammatic perspective views of embodiments ofbone replacements with a peripheral mechanical reinforcement.

FIGS. 7a and 7 b are diagrammatic perspective views of embodiments ofbone replacements with a tubular mechanical reinforcement.

FIG. 8a to 8 d are diagrammatic perspective views of bone replacementsshowing possible applications, especially for a tibial osteotomy ofaddition (FIGS. 8a to 8 c).

FIGS. 9a to 9 c are optical micrographs illustrating the replacement ofFIG. 8d, seen from above, from the side and in longitudinal section,respectively. In one particular embodiment, the macroporous ceramic isprepared from acrylic resin particles, such as polymethyl methacrylate(PMMA) particles, packed into a container.

It is also conceivable to use polyethylene, polymethacrylate orpolystyrene particles.

The common point between these compounds is especially theirpore-forming property.

DETAILED DESCRIPTION

In general, any organic compound may be chosen that has a low thermalexpansion in order to prevent deterioration of the compound during athermal cycle.

A thermoplastic polymer, capable of being thermoformed, willconsequently be chosen.

Moreover, in one particular embodiment, a polymer will be used that hasan at least partially amorphous structure, preferably a completelyamorphous structure, so as to avoid too great a volume increase duringthe heat treatment.

Finally, the pore-forming element must be able to degrade at lowtemperature with a negligible level of residual impurities and ofnon-corrosive decomposition products.

Typically, PMMA corresponds to a compound having all these properties.

Thus, in the rest of the description, reference will be made to PMMAparticles, it being understood that any other compound having theaforementioned properties may be used.

The PMMA particles used are in the form of beads which may havedimensions which are approximately identical to each other or differentdiameters.

In the latter case, it is conceivable to place in the bottom of thecontainer a certain number of small-sized balls on which larger-sizedballs rest. Such an arrangement will make it possible to obtain aceramic having different porosities.

It is also conceivable to arrange different layers of beads in thecontainer, the diameter of the beads increasing as they are beingpacked. Thus, a ceramic with a porosity gradient is obtained.

The spherical shape of the PMMA particles makes it possible inparticular to ensure that there are intimate and various contactsbetween the particles, to obtain a porosity of homogeneous morphologyand to control the final pore volume of the ceramic.

This is because PMMA particles have the particular feature of beingnon-deformable or of deforming only slightly, as indicated above.

As a result, the pores of the replacement obtained have dimensionsapproximately the same as those of the particles.

The PMMA beads used have, in one particular embodiment, a particle sizewhose distribution extends from a few microns to approximately 850microns.

In order to control the dimensions of the macropores of the ceramicobtained, the PMMA powder is subjected beforehand to a mechanicalscreening operation.

For the purpose, the PMA powder is passed between screens of differentmesh openings, so as to obtain batches of powder of relatively narrowparticle-size classes.

It is thus possible to select particle-size classes ranging from 0 to100 μm, from 100 to 200 μm, from 200 to 300 μm, from 400 to 500 μm, from500 to 600 μm, from 600 to 700 μm or from 700 to 850 μm.

It should be understood that narrower particle-size classes—from 190 to200 μm for example—may be selected.

It should be noted that some of the PMMA beads may be hollow.

It should be understood that the number, the shape and the distributionof the particles used depends on the shape of the mold and on theceramic that it is desired to obtain.

The container intended to receive the particles of organic compound mustbe able to withstand at least the thermal degradation temperature of thesaid compound.

In the present case in which an acrylic resin, and more particularlyPMMA, is used, this temperature is about 200° C.

Thus, the container is, for example, metallic, ceramic or polymeric.

In a second step, the PMMA particles undergo a thermoforming treatmentso as to ensure coalescence between the said particles.

In fact, an amorphous polymer, such as PMMA in particular, assumes arubbery consistency at a temperature above the glass transitiontemperature T_(g) of the said polymer.

It will be recalled that the glass transition temperature of PMMA isabout 110° C.

Thus, at a temperature above the glass transition temperature, thepolymer undergoes modifications of its macromolecules in order toachieve the rubbery consistency close to the viscous state. The polymercan therefore be easily modelled.

When the material is in this somewhat plastic state, contact between theparticles allows, by diffusion mechanisms, at least partial interlockingof some of the macromolecules contained in the various particles,resulting in them being welded together.

Once the desired state has been obtained, it is fixed by simplyreturning to room temperature.

This is because the viscosity of the material obtained then graduallyincreases when the temperature decreases.

The thermoforming process consists, in general, in homogeneously heatingthe particles, as a whole or on their surface, at a temperature abovethe glass transition temperature of the organic compound.

The PMMA thermoforming treatment may be divided into the followingsteps:

preheating the empty container at a temperature above that of the glasstransition of the PMMA, in this case above approximately 110° C.;

introducing the PMMA beads into the container;

forming and welding the beads until the end of cooling;

cooling to room temperature.

According to another embodiment, it is possible not to preheat thecontainer when empty but to heat it when filled.

The technique of thermoforming these pore-forming elements isreproducible and also applicable to edifices of a large area (severaltens of square centimeters) and of large volume (several tens of cubiccentimeters).

The effectiveness of the procedure for controlling the interconnectiondiameter is essentially diffusion-controlled, the quality of the weldswill depend on the temperature, the time and the intensity of theinterparticle contact.

In order to determine the optimum temperature for forming the polymer,the PMMA beads are introduced into a metal container preheated, forexample, to various treatment temperatures.

These temperatures, above the glass transition temperature, are 120° C.,150° C., 180° C. and 200° C., respectively.

These tests have made it possible to monitor the change in the bridgingbetween beads as a function of the thermoforming time. This analysis iscarried out by scanning electron microscopy.

These tests are carried out firstly on PMMA beads having a particle-sizedistribution of between 500 and 600 μm. For each manipulation, aconstant weight of beads equal to 5 grams is introduced into acylindrical container having a diameter of 26 millimeters.

For a treatment temperature of 120° C. and for heating times longer than20 hours, there is no cohesion between the beads. This temperature seemsto be insufficient to allow, in the times in question, diffusion andsufficient bridging between the polymer beads.

This interparticle cohesion becomes apparent at a temperature of 150° C.(see FIG. 5, in which particles of diameter between 500 and 600 μm haveundergone a treatment at 150° C. for 16 hours).

However, long times are necessary in order for the PMMA particles to bewelded together correctly. Scanning electron microscope analysis ofspecimens treated for 16 hours makes it possible to observe the contactarea between the beads and therefore to evaluate the effectiveness ofthe thermoforming operation.

This contact area corresponds to the future interconnection between themacropores of the bioceramic. In the present case, this line of contactremains discrete and has an estimated diameter of 100 μm.

A test temperature of 180° C. makes it possible, for short treatmenttimes, to achieve significant bridging between the beads.

The thermoformed PMMA particles thus form a monobloc structure having acertain number of spaces between the beads (see FIGS. 1 and 2).

Next, this monobloc structure is removed from the container and placedin a porous mold.

In the present embodiment, the mold is made of plaster.

It is also conceivable to use a mold made of ceramic, metal, resin orsimilar material.

The spaces between beads are then filed and impregnated with a densesuspension based on calcium phosphate in an aqueous medium.

This suspension, or slip, comprises hydroxyapatite (HA) or tricalciumphosphate (β TCP), or else a mixture of them each up to the 100 % level.

The suspension, thus consisting of powder and water, will gradually dryaround the monobloc structure because of capillary depression phenomenagenerated by the porosity of the plaster.

A “green” product—a two-phase mixture of ceramic and polymer beads—istherefore obtained.

In one particular embodiment of the invention, the mold has, in itswalls, a reservoir containing a sufficient amount of slip.

This reservoir allows the monobloc structure to be continuouslyimpregnated so that all the spaces are filled perfectly, this being sountil the slip has dried. This reservoir is used in combination with thecasting of the slip.

During casting of the suspension, a defloculation step is carried out inorder to achieve optimum deagglomeration of the suspension.

A calcium phosphate suspension, for example a hydroxyapatite suspension,is defloculated by a polyelectrolyte of the carboxylate type, widelyused in the ceramics industry; namely, ammonium polyacrylate (APa).

Under defined conditions (0.6% of APa and a pH of 11), varioussuspensions were tested using increasing HA contents, i.e. 82%, 84% and86%.

The viscosities of these slips were then determined at a velocitygradient of 100 s⁻¹.

The results show that a suspension of 82% solids has a relatively lowviscosity which allows the interstices between the PMMA spheres to becompletely filled.

It should be understood that suspensions with a lower concentration ofsolids may be used, especially in order to reduce the viscosity and makeit easier to impregnate the polymeric structure.

The “green” product obtained is then demoulded.

Next, in order to generate porosity, the “green” product undergoes aheat treatment at low temperature, but above the thermal degradationtemperature of the compound used (approximately 200° C. in the presentcase).

In the present embodiment, the temperature of this treatment is belowapproximately 300° C.

This heat treatment will therefore make it possible to remove the beads,by burning off all the organic matter, and therefore to generate voidsin their place.

Finally, in order to increase the cohesion and the rigidity of theproduct, the latter undergoes a sintering heat treatment at atemperature between 1100° C. and 1300° C.

A macroporous ceramic with controlled interconnections is thus obtained,this possibly being intended for bone replacement.

FIGS. 3 and 4 clearly indicate the control and the growth of theinterconnection diameter (small black holes) for a 500 μm porosity.

It should be understood that the plaster mold can have various shapes,whether simple or complex.

Thus, it may have, for example, an approximately parallelepipedal orcylindrical shape, these being simple shapes.

Furthermore, walls of various shapes may be provided inside such a moldso as to obtain a ceramic of complex shape.

It should be understood, in fact, that the shape of the plaster molddetermines that of the ceramic to be produced.

FIGS. 6a to 9 c show examples of complex configurations of the ceramicobtained, and therefore of the mold.

Thus, it is possible to provide dense parts allowing mechanicalreinforcement of certain regions of the replacement.

The polymeric edifice therefore does not include beads at the placewhere it is desired to have the dense part (s).

In FIGS. 6a to 6 c, the densest parts D are located on the periphery ofthe replacement, whether this be parallelepipedal (FIGS. 6a and 6 b) orcylindrical (FIG. 6c).

Dense parts inserted between macroporous parts may also be envisaged(not shown).

Furthermore, FIGS. 7a and 7 b show an embodiment of a cylindricalreplacement comprising a dense part D, a macroporous part M and a hollowpart C.

In FIG. 7a, the dense part D is inserted between the hollow part C andthe macroporous part M, while in FIG. 7b the dense part lies around theperiphery of the replacement.

Finally, FIGS. 8a to 8 c show replacements of complex shape, called“wedge”-shaped replacements, in which the dense or microporous parts aredepicted at D and the macroporous parts at M.

In these embodiments, the parts M are inserted between the parts D.

Such replacements can, for example, be used in the case of tibialosteotomy of addition.

FIG. 8d and FIGS. 9a to 9 c illustrate a replacement of frustoconicalgeneral shape, comprising an internal dense part D of cylindricalgeneral shape and an approximately frustoconical external porous part.

The dense parts D are obtained, for example, by generating lowerporosity, for example by using small-sized particles.

The strength of the replacement—and therefore its density—may also beincreased by increasing the spaces between the particles so as toincrease the amount of slip impregnated, or by removing the particlesfrom certain regions and by filling these regions with slip.

Of course, the invention is not limited to the embodiments that havejust been described

In fact, it is possible to envisage other ceramic shapes, and thereforeother mold shapes, or other particle shapes.

What is claimed is:
 1. A process for preparing a macroporous syntheticceramic said process comprising: introducing particles of a pore-formingorganic compound into a container; thermoforming said particles at atemperature above the glass transition temperature of the pore-formingorganic compound to provide a monobloc structure having coalescentparticles; contacting the monobloc structure with a calcium phosphatebased suspension; causing a liquid to diffuse from the monoblocstructure; removing the pore-forming organic compound to form a ceramicmaterial having pores; and sintering the ceramic material at atemperature sufficient to provide the macroporous synthetic ceramic. 2.The process according to claim 1, wherein said thermoforming consists ofhomogeneously heating the pore-forming organic compound at a temperatureabove the glass transition temperature of the organic compound.
 3. Theprocess according to claim 2, wherein the pore-forming organic compoundincludes a thermoplastic polymer.
 4. The process according to claim 3,wherein the pore-forming organic compound has an at least partiallyamorphous structure.
 5. The process according to claim 1 wherein saidthermoforming comprises: preheating the container, at a temperatureabove the glass transition temperature of the pore-forming organiccompound; introducing the particles into the container; welding theparticles until the end of cooling; cooling the particles to roomtemperature.
 6. The process according to claim 1, wherein thepore-forming organic compound is selected from polymethyl methacrylatepolymethacrylate, polystyrene, polyethylene and mixtures thereof.
 7. Theprocess according to claim 1, wherein said introducing includesintroducing particles having a substantially spherical shape into thecontainer.
 8. The process according to claim 1, wherein said suspensioncomprises hydroxyapatite or tricalcium phosphate (β TCP), or a mixturethereof.
 9. The process according to claim 1, wherein said removingincludes heating to a temperature greater than or equal to the thermaldegradation temperature of the pore-forming organic compound.
 10. Theprocess according to claim 1, wherein said removing includes heating toa temperature of about 1000° C. to about 1300° C.
 11. The processaccording to claim 1 wherein the container is formed of a metallic,ceramic or polymeric material able to withstand at least the thermaldegradation temperature of the pore-forming organic compound.
 12. Theprocess according to claim 1, wherein said monobloc structure isintroduced into a porous mold having a predetermined shape.
 13. Theprocess according to claim 1, wherein said porous mold is selected frommolds formed of material selected from plaster, ceramic, metal andresin.
 14. The process according to claim 1, wherein said microporoussynthetic ceramic has a pore diameter of between about 100 μm and 800 μmwith interconnections of from between about 0.1 and about 0.8 times saiddiameter.
 15. A synthetic ceramic obtained by the process according toclaim 1, and wherein said synthetic ceramic comprises a plurality ofmicropores having a diameter of between about 100 μg and about 800 μmand wherein said plurality of micropores have interconnections betweenabout 0.1 and about 0.8 times said diameter.
 16. The synthetic ceramicaccording to claim 15, provided with a macrostructure having a porositygradient.